The goal of this proposal is to determine the role of microglia in regulating the structure and function of the brain. Microglia are the resident immune cells of the central nervous system and display highly motile processes occupying a non-overlapping territory. Under physiological conditions, microglia may monitor the brain's microenvironment for damage signals and participate in the development and plasticity of neural circuits. Under pathological conditions, microglia undergo a series of morphological and functional changes, and may engage in containing tissue damage, phagocytosis and clearance of cellular debris, and/or the secretion of proinflammatory factors. Although microglia have been implicated in a multitude of physiological and pathological processes in the central nervous system, direct evidence of their functions remains elusive. Hampering efforts to delineate the role of microglia is the lack of tools to specifically perturb microglial function in vivo. I have recently generated mice with a targeted gene insertion allowing for the expression of tamoxifen- inducible Cre recombinase in CX3CR1 expressing microglial cells. This transgenic mouse line provides a molecular handle for the in vivo manipulation of microglia including deletion. By specifically ablating microglial cells in living mice, I will elucidate the role of microglia in anmal behavior and learning-dependent synaptic plasticity. As activated microglia are involved in almost every pathological condition in the brain, the proposed studies to identify the functions of microglia will provide important insights for the understanding and treatment of many neurological diseases. PUBLIC HEALTH RELEVANCE: Using the CX3CR1-CreER mouse that I have developed I will examine the role of microglia in synaptic structural plasticity as well as in learning and memory. The experiments proposed here will allow me to reveal important functions of microglia in the maintenance and remodeling of synapses. As activated microglia are involved in almost every pathological condition in the brain, including neuropsychiatric and neurodevelopmental disorders, the proposed studies will provide important insights for the understanding and treatment of many neurological diseases.